Inhalation of inorganic (e.g., mineral) dust is known to induce pathological changes in lung tissue leading to pneumoconiosis. Inorganic dust may include, but is not limited to silica, asbestos, cristobalite, man-made vitreous fibers, and the like. Pneumoconioses include silicosis, asbestosis, and Word Trade Center cough.
The inhalation of dust containing crystalline silica particles causes silicosis, an incurable lung disease which progresses even after dust exposure ceases. The World Heath Organization (WHO) estimates that over a million workers in the United States are exposed to silica dust annually, and that thousands worldwide die each year from silicosis (Verma et al., Occup. Environ. Med. 59:205-213, 2002). The pulmonary inflammation caused by silica inhalation is characterized by a cellular infiltrate and the accumulation of chemokines, cytokines (including TNF-, IL-1, and IL-6) and reactive oxygen species (ROS) in bronchoalveolar lavage (BAL) fluid (see, for example, Davis et al., Am. J. Respir. Cell Mol. Biol. 22:491-501, 2000; Huax et al., J. Immunol. 169:2653-2661, 2002).
Macrophages are the predominant immune cell type present in alveolar spaces where they play an important role in the lung pathology associated with silica inhalation (Davis et al. supra, 2002). The uptake of silica particles by macrophages triggers the production of reactive oxygen species (ROS) including H2O2 via the oxidative stress pathway, which in turn contributes to pulmonary damage and macrophage death (see, for example, Rimal et al., Curr. Opin. Pulm. Med. 11:169-173, 2005; Sayes, Toxicol. Sci. 97:163-180, 2007; Persson, Toxicol. Lett. 159:124-133, 2005; Giorgio, Nat. Rev. Mol. Cell Biol. 8:722-728, 2007). The dominant pathway by which silica-stimulated macrophages produce H2O2 involves the activation of NADPH oxidase (Fubini and Bubbard, Free Radic. Biol. Med. 34:1507-1516, 2007; Persson, supra, 2007; Giorgio et al, supra, 2007; Bedard and Krause, Physiol Rev. 87:245-313, 2007). In this pathway, cytoplasmic p47phox interacts with p67phox to form an active gp91 enzyme complex, with changes in ROS production correlating closely with levels of p47phox expression (see, for example, Teissier et al., Circ. Res. 95:1174-1182, 2005; Von and Brune, J. Immunol. 169:2619-2626, 2002).
There is a well established murine model of acute silicosis (Huax et al., J. Immunol. 169:2653-2661, 2002; Callis et al., J. Lab Clin. Med. 105:547-553, 1985; Hubbard, Lab Invest 61:46-52, 1989). While human disease typically progresses over many years (even decades), pulmonary inflammation in this model system develops rapidly and resolves over the course of several weeks. Nevertheless, this murine model shares important characteristics with human silicosis, including acute neutrophilic extravasation, increased protein in BAL, and progressive fibrosis (Callis et al., supra, 1985; Suzuki et al., Thorax 51:1036-1042, 1996; Faffe et al., J. Appl. Physiol 90:1400-1406, 2001). This murine model can be used to identify new agents for the treatment of silicosis.
Various forms of asbestos, such as chrysotile, crocidolite and amosite, have also been found to be toxic to mammals, particularly when inhaled. Inhalation of asbestos can induce one or more of inflammation and pulmonary fibrosis, either or both of which can lead to pulmonary disease such as respiratory impairment, as well as promote development of malignant pleural mesotheliomas. It is believed that inhalation of asbestos can induce pulmonary disease utilizing similar mechanisms as the inhalation of silica. For example, inhaled asbestos (for example, crystalline particles and/or fibers) typically contacts pulmonary macrophages which induces an inflammatory response characterized by production and release of toxic, reactive oxygen intermediates in the lung. Additionally, in vivo and in vitro studies show that alveolar macrophages, following exposure to asbestos, can release neutrophil chemotaxins such as interleukin (IL)-8 which can further contribute to inflammation in the respiratory tract.
Additional concerns for inhalation exposure to harmful inorganic dust have been raised by the collapse of the World Trade Center and the smoke from the associated fires. The steel columns of the World Trade Center were coated with sprayed asbestos as a fire retardant. Upon the collapse of the buildings, a fine white dust could be seen, the dust including pulverized concrete, tons of fine particles of asbestos and other inorganic dust such as particles containing one or more of silicon, sulfur, titanium, vanadium, and nickel. Some reports estimate that, as a result of the collapse, nearly 5,000 tons of asbestos were released in Manhattan. Those people in the vicinity of the collapsed buildings have been and may continue to be exposed to such inorganic dusts. Symptoms of exposure include chest tightness, bloody noses, sinus infections, and other respiratory ailments, including what is now termed as the “World Trade Center cough” (a persistent cough resulting from pulmonary inflammation). Nearly one in four firefighters who have been working at the Ground Zero site complain of having the World Trade Center cough. Of these firefighters, at least 10% have positive CAT scans showing pulmonary inflammation as a result of their exposure.
Bronchiolitis obliterans also can be initiated by inhalation of particles (inorganic dust, organic dust, and a combination thereof) in the small conducting airways of the respiratory tract, and which leads to inflammation of these airways that can ultimately result in irreversible airway obstruction. Examples of occupations that can develop such bronchiolitis through the inhalation of particles includes silo workers, textile workers, and workers in the food industry.
Hence, there is a need for a method for inhibiting pathogenesis induced by inhalation of particles (inorganic dust, organic dust, or a combination thereof). Specifically, there is a need for a method of therapy to treat or prevent pulmonary disease (including respiratory ailments) in an individual, wherein administered to the individual is a composition in an amount effective to reduce inflammation induced by inhalation of inorganic dust such as silica or asbestos.